VIDAZA® (azacitidine)

VIDAZA® (azacitidine)

Therapeutic indication

Adult patients not eligible for haematopoietic stem cell transplantations (HSCT)

Mechanism of action

VIDAZA® is believed to exert its antineoplastic effects by multiple mechanisms including cytotoxicity on abnormal haematopoietic cells in the bone marrow and hypomethylation of the DNA. The cytotoxic effects of VIDAZA® may results from multiple mechanisms, including inhibition of DNA, RNA and protein synthesis, incorporation into RNA and DNA, and activation of DNA damage pathways. Incorporation of VIDAZA® into DNA results in the inactivation of DNA methyltransferases, leading to hypomethylation of the DNA. DNA hypomethylation of aberrantly methylated genes involved in normal cell cycle regulation, differentiation and death pathways may result in gene re-expression and restoration of cancer-suppressing functions to cancer cells; The relative importance of DNA hypomethylation versus cytotoxicity or other activities of VIDAZA® to clinical outcomes has not been established.

Therapeutic indication

VIDAZA® is indicated for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantations (HSCT) with:

Intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS),
Chronic myelomonocytic leukaemia (CMML) with 10-29% marrow blasts without myeloproliferative disorder,
Acute myeloid leukaemia (AML) with 20-30% blasts and multi-lineage dysplasia, according to WHO classification,
Acute myeloid leukaemia (AML) with >30% marrow blasts according to the WHO classification

Reimbursement modalities

Administration and dosage

VIDAZA® treatment should be initiated and monitored under the supervision of a physician experienced in the use of chemotherapeutic agents. Patients should be premedicated with anti-emetics for nausea and vomiting.

The recommended starting dose for the first treatment cycle, for all patients regardless of baseline haematology laboratory values is 75mg/m² of body surface area, injected subcutaneously, daily for 7 days, followed by a rest period of 21 days (28-day treatment cycle).

It is recommended that patients be treated for a minimum of 6 cycles. Treatment should be continued as long as the patient continues to benefit or until disease progression.

Patients should be monitored for haematologic response/toxicity and renal toxicities ; a delay in starting the next cycle or a dose reduction as described after may be necessary.

Dose modifications

Toxicity

Dose adjustment due to haematological toxicity

Haematological toxicity is defined as the lowest count reached in a given cycle (nadir) if platelets ≤ 50,0 x 109/l and/or ANC ≤ 1 x 109/l.

Patients without reduced baseline blood counts (i.e. WBC ≥ 3,0 x 109/l and ANC ≥ 1,5 x 109/l, and platelets ≥ 75,0 x 109/l prior to the first treatment

If haematological toxicity is observed following VIDAZA® treatment, the next cycle of the therapy should be delayed until the platelet count and the ANC have recovered. If recovery is achieved within 14 days, no dose adjustment is necessary. However, if recovery has not been achieved within 14 days, the dose should be reduced according to the following table. Following dose modifications, the cycle duration should return to 28 days.

Nadir counts
% Dose in the next cycle, if recovery* is not achieved within 14 days
ANC (x 109/l)
Platelets (x 109/l)
≤ 1,0
≤ 50,0
50%
> 1,0
> 50,0
100%

* Recovery = count ≥ nadir count + (0,5 x [baseline count – nadir count])

Patients with reduced baseline blood counts (i.e. WBC < 3,0 x 109/l or ANC < 1,5 x 109/l or platelets < 75,0 x 109/l prior to the first treatment

Following VIDAZA® treatment, if the decrease in WBC or ANC or platelets from that prior to treatment is ≤ 50%, or greater than 50% but with an improvement in any cell line differentiation, the next cycle should not be delayed and no dose adjustment made.

If the decrease in WBC or ANC or platelets is greater than 50 % from that prior to treatment, with no improvement in cell line differentiation, the next cycle of Vidaza® therapy should be delayed until the platelet count and the ANC have recovered. If recovery is achieved within 14 days, no dose adjustment is necessary. However, if recovery has not been achieved within 14 days, bone marrow cellularity should be determined. If the bone marrow cellularity is > 50 %, no dose adjustments should be made. If bone marrow cellularity is ≤ 50 %, treatment should be delayed and the dose reduced according to the following table:

Bone marrow cellularity
% Dose in the next cycle, if recovery* is not achieved within 14 days

Recovery* ≤ 21 days
Recovery* > 21 days
15-50%
100%
50%
< 15%
100%
33%

* Recovery = count ≥ nadir count + (0,5 x [baseline count – nadir count])

Following dose modifications, the cycle duration should return to 28 days.

Hepatic impairment

No formal studies have been conducted in patients with hepatic impairment. Patients with severe hepatic organ impairment should be carefully monitored for adverse events. No specific modification to the starting dose is recommended for patients with hepatic impairment prior to starting treatment; subsequent dose modifications should be based on haematology laboratory values. VIDAZA® is contraindicated in patients with advanced malignant hepatic tumours.

 Renal impairment

VIDAZA® can be administered to patients with renal impairment without initial dose adjustment. if unexplained reductions in serum bicarbonate levels to less than 20mmol/l occur, the dose should be reduced by 50% on the next cycle. If unexplained elevations in serum creatinine or blood urea nitrogen (BUN) to ≥ 2-fold above baseline values and above upper limit of normal (ULN) occur, the next cycle should be delayed until values return to normal or baseline and the dose should be reduced by 50% on the next treatment cycle.

Drug-drug interactions

Based on in vitro data, VIDAZA® metabolism does not appear to be mediated by cytochrome P450 isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and glutathione transferases (GSTs) ; interactions related to these metabolizing enzymes in vivo are therefore considered unlikely.

Clinically significant inhibitory or inductive effects of VIDAZA® on cytochrome P450 enzymes are unlikely.

No formal clinical drug interaction studies with VIDAZA® have been conducted.

Adverse events of special interest

Haematologic adverse reactions

The most commonly reported (≥ 10%) haematological adverse reactions associated with VIDAZA®

treatment include anaemia, thrombocytopenia, neutropenia, febrile neutropenia and leukopenia, and were usually Grade 3 or 4. There is a greater risk of these events occurring during the first 2 cycles, after which they occur with less frequency in patients with restoration of haematological function. Most haematological adverse reactions were managed by routine monitoring of complete blood counts and delaying VIDAZA® administration in the next cycle, prophylactic antibiotics and/or growth factor support (e.g. G-CSF) for neutropenia and transfusions for anaemia or thrombocytopenia as required.

Infections

Myelosuppression may lead to neutropenia and an increased risk of infection. Serious adverse

reactions such as sepsis, including neutropenic sepsis, and pneumonia were reported in patients

receiving VIDAZA®, some with a fatal outcome. Infections may be managed with the use of anti-infectives plus growth factor support (e.g. G-CSF) for neutropenia.

Bleeding

Bleeding may occur with patients receiving VIDAZA®. Serious adverse reactions such as

gastrointestinal haemorrhage and intracranial haemorrhage have been reported. Patients should be

monitored for signs and symptoms of bleeding, particularly those with pre-existing or treatment related thrombocytopenia.

Hypersensitivity

Serious hypersensitivity reactions have been reported in patients receiving VIDAZA®. In case of an

anaphylactic-like reaction, treatment with VIDAZA® should be immediately discontinued and

appropriate symptomatic treatment initiated.

Skin and subcutaneous tissue adverse reactions

The majority of skin and subcutaneous adverse reactions were associated with the injection site. None of these adverse reactions led to discontinuation of VIDAZA®, or reduction of VIDAZA® dose in the pivotal studies. The majority of adverse reactions occurred during the first 2 cycles and tended to decrease with subsequent cycles. Subcutaneous adverse reactions such as injection site

rash/inflammation/pruritus, rash, erythema and skin lesion may require management with concomitant medicinal products, such as antihistamines, corticosteroids and non-steroidal anti-inflammatory medicinal products (NSAIDs). These cutaneous reactions have to be distinguished from soft tissue infections, sometimes occurring at injection site. Soft tissue infections, including cellulitis and necrotising fasciitis in rare cases leading to death, have been reported with VIDAZA® in the post marketing setting.

Gastrointestinal adverse reactions

The most commonly reported gastrointestinal adverse reactions associated with VIDAZA® treatment included constipation, diarrhoea, nausea and vomiting. These adverse reactions were managed symptomatically with anti-emetics for nausea and vomiting; anti-diarrhoeals for diarrhoea, and laxatives and/or stool softeners for constipation.

Renal adverse reactions

Renal abnormalities, ranging from elevated serum creatinine and haematuria to renal tubular acidosis, renal failure and death were reported in patients treated with VIDAZA®.

Hepatic adverse reactions

Patients with extensive tumour burden due to metastatic disease have been reported to experience

hepatic failure, progressive hepatic coma and death during VIDAZA® treatment.

Cardiac events

Data from a clinical trial allowing enrolment of patients with known history of cardiovascular or pulmonary disease showed a statistically significant increase in cardiac events in patients with newly

diagnosed AML treated with VIDAZA®.

Elderly population

There is limited safety information available with VIDAZA® in patients ≥85 years (with 14 [5.9%]

patients ≥85 years in AZA-AML-001 study).

Initial work-up before start of treatment

Liver function tests, serum creatinine and serum bicarbonate should be determined prior to initiation of therapy and prior to each treatment cycle; Complete blood counts should be performed prior to initiation of therapy and as needed to monitor response and toxicity, but at a minimum, prior to each treatment cycle.

Reference: SmPC Vidaza® (azacitidine) latest update 29/06/2017

                     Celgene Approval Number: BE-HEMA180006


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